The primary goal has been the elucidation of the structures of reactive metabolites responsible for the carcinogenic, cytotoxic and mutagenic activity of drugs, polycyclic aromatic hydrocarbons, and other environmental chemicals. The approach taken consists of: i) synthesis of primary and secondary oxidative metabolites, ii) study of the metabolism of the chemicals with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) evaluation of the mutagenicity and tumorigenicity of the synthetic metabolites, iv) elucidation of the roles of the. cytochrome P-450 system and epoxide hydrolase in modulating the mutagenicity of these metabolites, v) determination of the rates and products of reactions of arene oxides and diol epoxides with biopolymers and model compounds, and vi) search for agents capable of preventing the tumorigenicity of reactive metabolites. Synthetic studies have now made available optically pure bay-region 11,12-diol-13,14-epoxides of benzo[g]chrysene for testing of their mutagenic and tumorigenic activities. Comparative solvolytic studies of the bay-region 3,4-diol-1,2-epoxides of dibenz [ a, j ] anthracene with aza-analogs in which nitrogen has been substituted for CH at positions 7 or 14 have shown that nitrogen at position 14 has little effect (2 to 5-fold deceleration) on solvolytic reactivity in either the acid catalyzed or ph-independent (neutral to basic) regions whereas nitrogen at position 7 markedly decreases (23-fold) the acid-catalyzed reaction. A novel dicationic acidcatalyzed reaction mechanism has been observed in this latter case. Examination of the covalent bonding of the optically active bay-region-3,4-diol 1,2-epoxides of dibenz [ a, j ] anthracene to calf thymus DNA in vitro has allowed identification of a novel cytosine adduct in addition to the anticipated 16 adducts at adenine and guanine. Mutagenicity studies in bacteria and in Chinese hamster V79 cells have shown the 10,11-diol 8,9-epoxides of dibenz[a,h]acridine are more potent mutagens than the 3,4-diol 1,2-epoxides in accord with their differences in chemical reactivity.